For the purpose of treating a malignant tumor or viral disease, various cytidine metabolic antagonists have been developed, and cytarabine, gemcitabine and the like are clinically used as an anticancer agent, and zalcitabine, lamivudine and the like are clinically used as an anti-virus agent.
However, these cytidine metabolic antagonists are vulnerable to metabolism or excretion in vivo although they have strong activity in vitro, which often leads to no sufficient manifestation of the medicinal effects, or the necessity of higher dose. For example, gemcitabine has in vitro cytostatic activity comparable to a medicament such as paclitaxel and doxorubicin, which is an anticancer agent as well, but is clinically needed in a dose of 1000 mg/m2 per body surface area each time. It is contemplated that this is because the amino group of the cytosine base at the position 4 is subject to metabolism by a cytidine deamination enzyme, which is a metabolic enzyme of 2′-deoxycytidine, which leads to decrease of in vivo availability as gemcitabine (see Non-Patent Document 1).
Non-Patent Document 2 describes a polymer derivative in which polyglutamic acids having about 30,000 of the average molecular weight is bonded to cytarabine. However, as the case may be, the polymer derivative of a medicament may cause hyper-reactive reaction by the immune reaction, and in such a case, may not be administered repeatedly as a medicament.
Patent Document 1 discloses a polymer derivative in which a cytidine-based derivative is bonded to polyethylene glycols, and Non-Patent Document 3 discloses a polymer derivative in which both ends of polyethylene glycols are substituted with aspartic acid in a branched shape, and cytarabine is bonded thereto. However, with these polymer derivatives, only 1 to 8 molecules or so of the medicament may be bonded to per one molecule of the polyethylene glycols, and thus the total amount of the polymer becomes large in order to administer the effective amount. Furthermore, the release of the medicament from these polymer derivatives is dependent in a portion on the hydrolysis reaction by an enzyme in vivo, and the clinically therapeutic effects are likely to be greatly influenced by individual difference of patients.
Patent Document 2 describes that a molecule, in which a medicament is bonded to a block copolymer from condensation of polyethylene glycols and polyaspartic acid, forms a micelle to become a medicine. In addition, Patent Document 3 describes a polymer carrier, which is a polymer vehicle in which a hydrophobic substance is bonded to the side-chain carboxy group of a block copolymer of polyethylene glycols and polyacidic amino acid. Furthermore, Patent Document 4 describes a polymer derivative in which an anticancer agent is bonded to the side-chain carboxy group of glutamic acid of a block copolymer from condensation of polyethylene glycols and polyglutamic acid. However, the Patent Publications 2 to 4 do not describe a cytidine metabolic antagonist as a medicament to be bonded.
Patent Document 5 describes a polymer derivative in which the side-chain carboxy group of a block copolymer of polyethylene glycols and polyglutamic acid is amide-bonded to an amino group of a cytidine metabolic antagonist. In addition, Patent Document 6 describes a polymer derivative in which the side-chain carboxy group of a block copolymer of polyethylene glycols and polyglutamic acid is ester-bonded to the hydroxy group of a nucleoside derivative that is a nucleic acid-based metabolic antagonist. However, in these documents, the cytidine metabolic antagonist is directly bonded to the carboxy group of the copolymer of the polyethylene glycol and polycarboxylic acid, but the cytidine metabolic antagonist is not bonded via any linker.
Patent Document 7 describes a polymer derivative in which a nucleoside derivative that is a nucleic acid-based metabolic antagonist is bonded via a linker having high hydrophobicity to the side-chain carboxy group of a block copolymer of polyethylene glycols and polyglutamic acid. However, this linker is not a structural moiety of succinic acid monoamide, and the polymer derivative is not a system to release the medicament along with formation of an imide.